1. Field of the Invention
The present invention provides highly efficient, catalytic methods for N-alkylation of indole derivatives, more specifically the method provides N-methylindole and N-benzyl-indole derivatives.
2. Description of Related Art
N-Methylindole derivatives, such as indole alkaloids are important natural products that exhibit a wide array of biological activities. For example, affinisine has been shown to produce delayed intention tremors, marked central nervous system (CNS) depressant activity, ataxia, hypothermia and bradypnea (Liu et al., Tetrahedron Lett., 2000, 41, 6299), and a synthetic pentacyclic indole analog has revealed antitumoral properties (Christophe et al., Tetrahedron Lett. 1998, 39, 9431).
Common approaches to the synthesis of N-alkylindole derivatives typically require a two-step protocol: (1) formation of an active indole anion by stoichiometric amount of a strong base; and (2) reaction of the resulting anion with a toxic and hazardous alkylating agent such as methyl iodide, dimethyl sulfate, benzyl chloride or benzyl bromide (e.g. Hilton et al., J. Chem. Soc., Chem. Commun. 2001, 209; Tratrat et al., J. Org. Chem. 2000, 65, 6773; and Ottoni et al., Tetrahedron 1998, 54, 13915). Improved processes have been recently published utilizing non-toxic reagents, however, under harsh and stoichiometric conditions (Bergman et al., Tetrahedron 1990, 46, 6113). It has been reported that dimethyl carbonate may be employed effectively under milder conditions to N-methylate indole derivatives, however, these methods still demand the use of a stoichiometric amount of a base to achieve reasonable process efficiency (Shieh et al., Organic Lett. 2001, 3, 4279; and PCT Application No. WO 01/81305). Thus, development of an efficient, safe, and ecologically friendly methods for alkylation of indoles still constitutes an important challenge.